Clinical genomics

The goal is to demonstrate that integration of genomics into the clinical care of refractory epilepsy patients will significantly improve their healthcare and show that this can be delivered using available resources effectively and efficiently. This project involves screening for genes, to see if we can identify a cause for the epilepsy.

The mission will be accomplished by creating a diagnostic and management algorithm which incorporates accessible genomic testing for the treating neurologist, a multi-disciplinary approach for report generation, enabling a clinically meaningful report to the neurologists as well as individualised reports to patients.

Functional genomics

The rate of gene discovery however, has outpaced our ability to understand the pathophysiology of gene variants and how they relate to phenotypes. There is an imperative need to develop high-throughput functional analyses, such as induced pluripotent stem cells and cerebral organoids (3D neuronal networks), that are able to model the combinatorial impact of genetic variants observed in patients and their functional impact. A further proof of principle approach would involve introducing some common genetic variants into a control pluripotent cell line, to determine which are of functional significance.

Epigenomics

Epigenetics is the study of changes in gene expression without changes to the DNA sequence. The most studied epigenetic mechanism is DNA methylation. Twins are an ideal paradigm for differentiating between the three major components of phenotypic variation: genetics, shared, and non-shared environment. The discordant monozygotic twin model further provides an elegant study design that controls for shared genetic and environmental factors, enabling focus on the non-shared environment, the largest component of risk variance across all chronic disorders. Twin models are ideal for understanding the epigenetic and genetic landscape in epilepsies.